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  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
  • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
  • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
  • C07D451/06—Oxygen atoms
  • C07D451/12—Oxygen atoms acylated by aromatic or heteroaromatic carboxylic acids, e.g. cocaine
• • C—CHEMISTRY; METALLURGY
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
• • C—CHEMISTRY; METALLURGY
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  • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
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  • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
• • C—CHEMISTRY; METALLURGY
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  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/08—Bridged systems

Definitions

• This invention relates to new uses and modes of administration of serotonin 5HT 3 antagonists and also to mono- or bicyclic carbocyclic, or heterocyclic carboxylic, acid ester and amides and imidazolyl carbazols, e g., imidazolylmethylcarbazols.
• the compounds may be used in any pharmaceutically acceptable form, including the free base and at least for the esters and amides, in acid addition and quaternary ammonium salt forms.
• esters,and amides and imidazolyl carbazols have in general serotonin 5HT 3 antagonist activity which may have not been previously recognized.
• esters, amides and carbazols are in general known for example from Belgian patents 897117, 900425 and 901274. These compounds are described therein as being serotonin 5HT 3 receptor antagonists or serotonin M receptor antagonists (serotonin M receptors have been reclassified as 5HT 3 receptors).
• the compounds are for treatment as anti-migraine agents, anti-arrhythmics, and for treatment of serotonin-induced gastro-intestinal disorders including emesis, e.g. induced by anti-cancer agents.
• the present invention provides use of a mono- or bicyclic carbocyclic, or cyclic heterocyclic carboxylic acid ester or amide e.g. of a cyclic alcohol or amine, containing nitrogen as a ring atom, or a serotonin 5HT 3 antagonist or an imidazolyl carbazol, for the treatment of stress-related psychiatric disorders, rhinitis, or serotonin-induced nasal disorders or lung embolism, or coadministration with another active agent to increase the biovailability thereof, or for nasal administration or for the manufacture of a medicament suitable therefor.
• the invention also provides a method of treating a subject with any of the indications which comprises administering to a subject in need of such treatment a compound of the invention.
• the invention also provides:
• a process for the production of a pharmaceutical composition adapted for the treatment of stress-related psychiatric disorders, forincreasing viligance, for the treatment of rhinitis, or for serotonin-induced nasal disorders or lung embolism which comprises working up a compound of the invention with pharmaceutical carriers and diluents to manufacture unit dosage formulations for said indications.
• a process for the production of a nasal composition which comprises working up a compound of the invention with an appropriate nasal carrier, and optionally incorporating a surface active agent and optionally filling the resultant composition into a nasal applicator.
• a process for the production of a pharmaceutical composition having improved bioavailability which comprises working up a compound of the invention, e.g. a compound of formula I or Ia as defined hereinafter, with another active agent, e.g. a peptide, and if desired formulating as a unit dosage form.
• a compound of the invention e.g. a compound of formula I or Ia as defined hereinafter
• another active agent e.g. a peptide
• the ester or amide is an ester or amide of a cyclic alcohol, or amine, containing nitrogen as a ring atom.
• the heterocycle is a bicyclic heterocycle preferably aromatic.
• the ester or amide or serotonin HT 3 antagonist is a dicarboxyclic or heterocyclic carboxylic acid ester, or carboxylic acid amide, of a piperidinol containing an alkylene bridge, or of piperidylamine containing an alkylene bridge, or of an ester, or amide, of a substituted benzoic acid, or of a piperidinol or piperidylamine containing an alkylene bridge, with the proviso that in each benzoic acid amide the alkylene bridge of the piperidyl ring is bonded to the nitrogen atom and to a cyclic carbon atom.
• ester or amide or serotonin 5HT 3 antagonist or imidazolcarbazol is a compound of formula I
• A is ##STR1## wherein the free valence is attached to either fused ring in formula II, IIa, IIb, IIe or IV,
• X--Y is --CH ⁇ CH--, --O--CH 2 -- or --N ⁇ CH--,
• Z is --CH 2 --, --NR 3 --, --O-- or --S--,
• R 1 and R 2 are independently hydrogen, halogen, (C 1-4 )alkyl, (C 1-4 )alkoxy, hydroxy, amino, (C 1-4 )alkylamino, di(C 1-4 )alkylamino, mercapto or (C 1-4 )alkylthio,
• R 3 is hydrogen , (C 1-4 )alkyl, acyl, (C 3-5 )alkenyl, aryl or arylalkyl, and
• R 4 to R 7 are, independently, hydrogen, amino, nitro, (C 1-4 )alkylamino, di(C1,4)alkylamino, halogen, (C 1-4 )alkoxy, (C 1-4 )alkyl, (C 1-4 )alkanoylamino, pyrrolyl, sulfamoyl, or carbamoyl,
• B is --CO-- or --SO 2 --
• C is --O-- or --NH--, a bond
• D is a group of formula ##STR2## wherein n is Z, 3 or 4 ##STR3## wherein R 8 is hydrogen, (C 1-7 )alkyl, (C 3-5 )alkenyl or aralkyl, and in formula VIII the bond is in position 3 or 4,
• D when B is CO, additionally D may be a group of formula ##STR4## wherein t is 1 or 2, and R 8 is as defined above, ##STR5## wherein the bond is in the position 3 (*) or 4 [*], ##STR6## wherein 1 is 2 or 3, ##STR7## where Z is (C 1-4 )alkoxy, ##STR8## wherein R 9 to R 12 are independently hydrogen or (C 1-4 )-alkyl and m is 0, 1 or 2 and n, o, p independently are 0 or 1, ##STR9## wherein q is 2 or 3, and R 13 and R 14 independently are (C 1-4 )alkyl, ##STR10## wherein the bond is in position 3 or 4, ##STR11## and R 8 is as defined above, in free base form, acid addition salt form or quaternary ammonium salt form,
• R 15 is hydrogen, (C 1-10 )alkyl, (C 3-9 )cycloalkyl, (C 3-6 )alkenyl, phenyl or phenyl (C 1-3 )alkyl and one of the groups R 16 , R 17 and R 18 is hydrogen, (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 2-6 )alkenyl or phenyl (C 1-3 )alkyl and the others independently are hydrogen or (C 1-4 )alkyl.
• the compound is of formula I wherein A is chosen from formula II, III, IV and V, R 3 is other than acyl, C is --O-- or --NH-- and D is chosen from formula VI to XVIII,
• R 1 ' and R 2 ' independently of one another, are hydrogen halogen, (C 1-4 )alkyl, (C 1-4 )alkoxy, hydroxy, amino, (C 1-4 )alkylamino, di(C 1-4 )alkylamino, mercapto or (C 1-4 )alkylthio, and
• R 3 ' is hydrogen, (C 1-4 )alkyl, (C 3-5 )alkenyl, aryl or aralkyl, or a group of formula III' ##STR14## wherein signifies CO--SO 2 R 4 ' to R 7 ', independently of one another, are hydrogen, amino, nitro, (C 1-4 )alkylamino, di(C 1-4 )alkylamino, halogen, (C 1-4 )alkoxy, (C 1-4 )alkyl, (C 1-4 )alkanoylamino or pyrrolyl,
• R 8 ' is hydrogen, (C 1-7 )alkyl, (C 3-5 )alkenyl or aralkyl, or a group of formula VIII, ##STR16## with the proviso that when A is a group of formula III and B is --NH--, then D signifies a group of formula VIII.
• a further group comprises formula I wherein A is a group of formula II or III wherein B ⁇ --CO--, C ⁇ --O-- or --NH-- then D is a group of a group of formula VII, IX, X, XI or one of XIII to XXV or A is group of formula IIa, IIb, IIc, IId, IIe, IV or V and B, C and D are as defined above.
• Another group of compounds of formula I comprises compounds wherein A is formula II or III, wherein R 4 to R 7 are other than sulfamoyl or carbamoyl, D is VI or VIII with the proviso when A is III and C is --NH-- and D is VIII.
• Preferred compounds include:
• the compounds of formula I is a group of formula II, in particular Z is NR 3 , O, or S.
• the compound of formula I is a group of formula III.
• a sub-group D is VI.
• a 2nd sub-group D is VII.
• a 3rd sub-group D is VIII.
• a 4th sub-group D is IX.
• a 5th sub-group D is X.
• a 6th sub-group D is XI.
• a 7th sub-group D is XII.
• a 8th sub-group D is XIII.
• In a 9th sub-group D is XIV.
• a 10th sub-group D is XV.
• a 11th sub-group D is XVI.
• a 12th sub-group D is XVII.
• a 13th sub-group D is XVIII.
• D is VI or VIII.
• a preferred group of compounds comprises a compound wherein A is a group of formula II wherein R 1 and R 2 are independently hydrogen, halogen, (C 1-4 )alkyl or alkoxy; R 1 is in position 4 or 5;
• R 3 is hydrogen, acetyl or (C 1-4 )alkyl and the corresponding bond is in position 3, 4 or 5,
• the present invention also provides novel compounds of formula Ib
• A' is a group of formula II, wherein R 1 , R 2 and Z are as defined above, C' is --O-- or --NH-- and D' is a group of formula XIX, wherein q, R 13 and R 14 are as defined above,
• A' is a group of formula III, wherein R 4 and R 6 are each hydrogen, and R 5 and R 7 are each chlorine, C' is --O-- and D' is one of the groups of formula VI, wherein n is 3 and R 8 is as defined above or VIII,
• A' is a group of formula II, wherein R 1 , R 2 and Z are each as defined above, C' is --O-- and D' is a group of formula XX, wherein the bond is in position 3 or 4,
• A' is a group of formula IIa, wherein R 1 , R 2 and Z are as defined above, C' is --NH-- or --CH 2 -- and D' is a group of formula VI, wherein R 8 is as defined above or VIII, wherein the bond is in position 3 or 4,
• A' is a group of formula IIb, wherein R 1 , R 2 and Z are as defined above, C' is --O-- and D' is a group of formula VI, wherein R 8 is as defined above,
• A' is a group of formula IIc, wherein R 1 , R 2 and Z are as defined above, C' is --O-- and D' is a group of formula VI, wherein R 8 , is as defined above,
• A' is a group of formula IId, C' is --O-- and D' is a group of formula VI,
• A' is a group of formula II, wherein R 1 , R 2 and Z are as defined above, C' is --NCH 3 --, and D' is a group of formula VI, wherein R 8 is as defined above,
• A' is a group of formula II, wherein R 1 , R 2 and Z are as defined above, C' is --O-- and D' is a group of formula XXI,
• A' is a group of formula III, wherein R 4 -R 7 are as defined above, C' is --NH-- and D' is a group of formula XXII, wherein R 8 is as defined above,
• A' is a group of formula II, wherein R 1 is 6-hydroxy- or 6-methoxy- or 5-methyl, R 2 is hydrogen and Z is --NH--, C' is --O-- and D a group of formula VI, wherein R 8 is as defined above,
• A' is a group of formula II, wherein R 1 , R 2 and Z are as defined above, C' is --O-- and D' is a group of formula XXIII, wherein R 8 is as defined above,
• A' is a group of formula II, wherein R 1 , R 2 and Z are as defined above, C' is --O-- and D' is a group of formula XXII, wherein R 8 is as defined above,
• A' is a group of formula IIe, wherein Z is as defined above, C' is --O-- and D' is a group of formula VI, wherein R 8 is a defined above,
• A' is a group of formula II, wherein R 1 , R 2 and Z are as defined above, C' is a bond and D' is a group of formula XXIVa, wherein R 8 is as defined above,
• A' is a group of formula II, wherein R 1 , R 2 and Z are as defined above, C' is a bond and D' is a group of formula XXIVb, wherein R 8 is as defined above,
• A' is a group of formula II, wherein R 1 and R 2 are as defined above, Z is N-acyl, C' is --O-- and D' is a group of formula VI, wherein R 8 is as defined above,
• A' is a group of formula II, wherein R 1 is hydroxy, R 2 is hydrogen and Z is --NH--, C' is --CH 2 -- and D' is a group of formula VI, wherein R 8 is as defined above,
• the present invention also provides a process for the production of a compound of formula Ib as defined above in free base form or in acid addition salt form or in quaternary ammonium salt form, which includes the step of:
• A' is as defined above, or a reactive derivative thereof, or a precursor of the acid or reactive derivative with an appropriate compound of formula XXXI
• A' is as defined above, and Hal is chlorine, bromine or iodine, with an appropriate compound of formula XXXIII
• D' is as defined above, in free base or protected form under conditions of a Grignard reaction, and removing any protecting group present
• the reactions may be effected in conventional manner, e.g. as described in the patent publications referred to above or in analogous manner for known compounds.
• the processes may be generally effected in an inert solvent at e.g. from about -30° C. to about 200° C. using conventional reagents.
• Compounds of formula Ib wherein Z is N-acyl may be conveniently produced according to process e), in conventional manner e.g. by acylating a compound as disclosed e.g. in Belgian Patent No. 897,117 with an acylating agent such as acetic acid anhydride or benzyl chloride.
• the resultant compounds may be converted in conventional manner into acid addition salt form and back into free base forms and also converted in conventional manner into the quaternary ammonium salt form.
• the compounds of the invention are useful for the treatment of stress-related psychiatric disorders, including stress related-social phobias and social withdrawal, affective disorders, psychoses, especially manic depressive disorders and promote approach-oriented behaviour in behaviour perturbed by stress.
• the compounds of the invention also increase vigilance, e.g. in geriatrics.
• mice have been carried out on the effects of the compounds of the invention on approach-oriented behaviour in mice.
• the compounds increase approach-oriented behaviour in stress-situations normally inhibitory to social responses.
• situations involving unfamiliar surroundings, contact with foreign aggressive opponents, competition for food were created under reversed lighting conditions whereby observations were performed during the darkphase.
• untreated rodents exihibit high levels of flight, particularly depressive ambivalence and escape behaviour, but low levels of social behaviour involving approach activity.
• Anxiolytics like diazepam reduce the ambivalent behaviour and can increase social behaviour.
• certain antidepressants e.g. bupropion and impramine, but also atypical anxiolytics e.g. bupropion as well as the compounds of the invention, increase approach-oriented social behaviours.
• Intruders receiving oral doses of benzodiazepines show less of these defensive activities and more approach-oriented behaviour (A. K. Dixon Triangle 1982, 21, 95-105; M. Krisak, Br. J. Pharmacol 1975, 55, 141-150), e.g. investigation, aggression and sexual activity.
• the compounds of the invention are administered 1 hour before the encounter per-orally at from about 0.1 to about 10 mg/kg. Groups of 8 mice pairs are used. The frequency and duration of social and non-social behaviour of the mice were recorded using ethological techniques.
• the compounds increase social oriented activity.
• Study A was modified using a large cage (59 ⁇ 38.5 ⁇ 20 cm) which allowed greater freedom of movement so that elements of defense could be separated more clearly from the approach-oriented social activities.
• the compounds of the invention were given i.p. at doses from about 0.01 to about 100 microgram/kg 45 minutes before the encounter.
• benzodiazepines increase eating behaviour more than social interactions.
• Antidepressants may increase such social activities.
• the compounds of the invention increase approach-oriented social behaviour, more than eating.
• Compound E at a dose of 0.1 mg/kg p.o. given 2 hours before the encounter increased, relative to controls, the frequency (54 percent) and duration (321 per cent) of social interactions. In contrast frequency of feeding increased by only 4 per cent and their duration 55 per cent.
• SAP's which signify amibivalence.
• Drugs which have putative anxiolytic reactions e.g. benzodiazepines, barbiturates, and buspirone reduce the incidence of SAP's (H. P. Kasermann, Psychopharmacology 1986, 89, 31-37).
• the compounds of the invention administered p.o. at a dose of from about 0.1 to about 10 mg/kg. 2 hours before the test reduce the duration of SAP when placed on the platform for 2 minutes under conditions where no other mice are present.
• mice subjected to a novel environment e.g. on transferring them from one room to another via a trolley, exhibit a rise in plasma corticosterone typical of stress related disturbances which are reduced by benzodiazepines and barbiturates (Lahti R. A. Borsulm C., Res. Comm.Chem.Path.Pharm.11: 596-603; G. Le Fur et al., J.Pharm.exp.Ther. 211: 305-308). Reduction is observed with the compounds of the invention at from about 0.1 to 10 mg/kg p.o. compound E reduces such stress-induced corticosterone at about 1 to 10 mg/kg p.o. whilst lower doses from about 0.1 to about 0.3 mg/kg increase basal plasma levels of this hormone. This profile is analogous to that observed with diazepam.
• corticosterone increases in corticosterone, thus indicating a potential use for the compounds in disorders of vigilance e.g. geriatric illnesses.
• the compounds of the invention may be administered in similar manner to known standards, e.g. bupropion.
• the preferred compound E and bupropion have been found to have a pronounced effect on promoting social interaction under stress related conditions.
• compound E increased the mean frequency of social interactions in the competitive feeding experiment study c) by 54 per cent at 0.01 mg/kg compared to bupropion provoking an increase of 179 per cent at 2.5 mg/kg. It is indicated that compound E will be useful in the treatment of stress-related psychiatric disorders at a daily oral dose of from 0.1 mg which could be increased up to 50 mg.
• A is a group of formula II or III and B is --CO--, C is --O-- or --NH-- and D is a group of formula VII, IX, X, XI and one of XIII to XXV, and (ii) A is a group of formula IIa, IIb, IIc, IId, IIe, IV or V as an anxiolytic or in the manufacture of a medicament available therefor also forms part of the present invention and is also shown by the above testing.
• the appropriate dosage will, of course, vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results are indicated to be obtained at daily dosages from about 0.001 mg/kg to about 50 mg/kg animal body weight. In humans, an indicated daily dosage is in the range from about 0.1 mg to about 50 mg of a compound of the invention conveniently administered, for example, in divided doses up to four times a day.
• the present invention provides use of a mono or bicyclic carbocyclic or heterocyclic carboxylic acid esters or amides of a cyclic alcohol or amine containing nitrogen as a ring atom in free base form or in acid addition salt or quaternary ammonium salt form as 5-HT 3 antagonists in the manufacture of a medicament suitable for the treatment of serotonin induced psychiatric disorders, e.g. when chosen from one of the following: anxiety, social withdrawal, affective disorders, psychoses and other stress-related illnesses i.e., disorders of vigilance, e.g. geriatric illnesses
• Preferred compounds include:
• the compounds of the invention may be administered in free base form or, when they can be formed, in pharmaceutically acceptable acid addition salt form or in a quaternary ammonium salt form.
• Such salts may be prepared in conventional manner and are in general known. They exhibit the same order of activity as the free base form and pharmaceutical compositions comprise a compound of the invention in free base or pharmaceutically acceptable acid addition salt form or quaternary ammonium salt form in association with a pharmaceutical carrier or diluent.
• Such compositions may be manufactured in conventional manner.
• the compounds may be administered by any conventional route, in particular enterally, preferably orally, e.g. in the form of tablets or capsules or parenterally, e.g. in the form of injectable solutions or suspensions.
• Suitable pharmaceutical carriers and diluents for oral administration include polyethylene glycol, polyvinylpyrrolidone, mannitol, lactose etc. granulating agents, and disintegrating agents such as starch and algenic acid, binding agents such as stearic and gelatine, and lubricating agents such as magnesium stearate, stearic acid and talc.
• Suspensions may contain conserving agents like ethyl p-hydroxy-benzoate, and suspending agents such as methyl-cellulose, tenside etc.
• the compositions are preferably bufferred, aqueous solutions (pH between 4 and 5).
• the compounds of the invention may be administered nasally and have an especially interesting resorption profile.
• the compounds of the invention increase the nasal resorption or bioavailability of other active agents such as peptides particularly when administered by the nasal route.
• the compounds of the invention moreover are useful in the treatment of rhinitis and serotonin-induced nasal disorders as indicated by an inhibition of nasal secretions on administration of the compounds of the invention.
• the bioavailability and pharmacokinetic profile of the compounds of the invention may be determined in conventional manner, e.g. in mammals including rhesus monkeys and humans.
• concentrations of the compounds of the invention in the blood plasma after administration of from about 0.01 to about 10 mg/kg to each nostril, e.g. 7.5 mg in the case of compound E, locally to the nasal mucous membrane, e.g. as a spray, may be determined in conventional manner by e.g. radioimmunoassay or HPLC methods.
• the compounds of the invention are rapidly absorbed, e.g. over about 10 minutes.
• Nasal secretions are also inhibited. Additionally, the compounds of the invention when administered, e.g. at a dose of from 0.01 to 10 mg/kg with a therapeutically effective dosage of another compound, e.g. a peptide, such as salmon calcitonin increases the absorption thereof.
• another compound e.g. a peptide, such as salmon calcitonin increases the absorption thereof.
• an indicated daily dosage for oral administration is in the range from about 5 mg to about 300 mg of a compound of formula I conveniently administered, for example, in divided doses up to four times a day, e.g. in the range of about 40 mg p.o. in the case of compound E.
• the appropriate dosage will, of course, vary depending upon, for example, the active agent of the compound of the invention and other active agent employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results are indicated to be obtained at daily dosages from about one half to one tenth the usual dose of the other active agent. The compound of the invention is indicated to be administered at about one half to one tenth the usual dose.
• the compounds of the invention may be administered for the rhinitis and nasal serotonin-induced disorders and for co-administration with another active agent, e.g. a peptide, by any conventional route, in particular enterally, preferably orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions.
• a conventional route in particular enterally, preferably orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions.
• enterally preferably orally, e.g., in the form of tablets or capsules
• parenterally e.g., in the form of injectable solutions or suspensions.
• injectable solutions or suspensions e.g., injectable solutions or suspensions.
• the appropriate dosage will, of course, vary depending upon, for example, the compound of the invention employed, the host, and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at daily dosages from about 0.001 mg/kg to about 10 mg/kg animal body weight. In humans, an indicated dosage per actuation is in the range from about 0.01 mg to about 1 mg of a compound of the invention conveniently administered, for example, in doses up to four times a day.
• a compound according to the invention is indicated to be administered to the body nasally in a dosage of 0.13 to 0.4 mg kg body weight, i.e. ca. 10 to 30 mg or 1 to 3 pumps of the nasal spray per patient, and in order to control arrhythmia, it should be given in a dosage which is ca. 10 times higher, i.e. from 1.3 to 4 mg per kg body weight or 100 to 300 mg, or resp. 10 to 30 pumps of the nasal spray per patient.
• the compound E is the preferred compound for the rhinitis and nasal route administration. It is indicated that compound E may be administered at daily dosages of about 0.1 mg nasally to humans.
• the compounds of the invention may be administered nasally in any pharmacologically active form, e.g. in free base form, in acid addition salt form or in quaternary ammonium salt form.
• the nasal mode of administration creates a simple method of administration which rapidly gives results and can be easily carried out by the patient himself, e.g. by administering a liquid form for nasal administration, for example a nasal spray or drop solution using a nasal applicator, or by inserting a gelatinous sponge or lyophilisate soaked in the active substance, or by blowing the galenic form in powder form into the nostrils.
• a liquid form for nasal administration for example a nasal spray or drop solution using a nasal applicator
• a gelatinous sponge or lyophilisate soaked in the active substance or by blowing the galenic form in powder form into the nostrils.
• the compounds of the invention may be present in the liquid form for nasal administration in a proportion of 1 to 30%, preferably 5 to 20%, especially 10 to 15% (weight/volume).
• the present invention accordingly provides also a liquid form for nasal administration, containing
• the proportion of benzalkonium chloride in the compositions according to the invention is preferably ca. 0.002 to ca. 0.02, especially ca. 0.01% (weight/volume) of the total composition.
• the above-mentioned forms of administration may be administered to the nasal mucous membrane, e.g. as drops or as a spray. As described hereinafter, however, they are preferably administered as a spray, i.e. as finely dispersed droplets.
• a gelatinous sponge SPONGOSTAN
• lyophilisate a gelatinous sponge
• the liquid diluent or carrier employed is conveniently water (pharmaceutical grade).
• An aqueous salt solution is preferred in particular.
• the liquid forms for nasal administration according to the invention are formulated such that they allow administration to be effected nasally. With this in mind, they can e.g. also contain minimal amounts of further desired components or excipients, e.g. additional preservatives, or e.g. ciliary stimulants such as caffeine.
• the liquid forms for nasal administration according to the invention preferably have a pH value of 5.5 to 6.
• the liquid forms for nasal administration should also have an appropriate isotonicity and viscosity. They preferably have an osmotic pressure of ca. 260 to ca. 380 mOsm/liter.
• the desired viscosity of the compositions according to the invention depends on the relevant form of administration, e.g. whether nasal drops or a nasal spray are administered. For nasal drops, a viscosity of ca. 2 to ca. 40 ⁇ 10 -3 Pa.S is suitable. For nasal sprays, a viscosity of less than 2 ⁇ 10 -3 Pa.S is suitable.
• the liquid forms for nasal administration may also contain further components, especially conventional pharmaceutically available surface-active agents.
• surface-active compounds for example polyoxyalkylene ethers of higher alcohols, e.g.
• RO signifies the radical of a higher alkanol, especially a higher alkanol such as lauryl or cetyl alcohol, or of an alkylphenol, or a sterol, especially lanosterol, dihydrocholesterol or cholesterol, as well as mixtures of two or several such ethers.
• Preferred polyoxyalkylene ethers which can be used for the present invention are polyoxyethylene- and polyoxypropylene-ethers (i.e. wherein n in the above-mentioned formula is 2 or 3), especially lauryl-, cetyl- and cholesterylpolyoxyethylene- and -polyoxypropylene-ethers, as well as mixtures of two or several such ethers.
• Especially suitable polyethers for use according to the invention are those in which the average value of the recurring units in the polyoxyalkylene component (x in the above formula) lies between 4 and 75, especially between 8 and 30 and particularly between 16 and 26.
• the polyethers may be obtained in accordance with known methods. A large choice of such products is available commercially and is sold e.g. by Amerchol under the trade name Solulan (R), by KAO Soap, ICI and Atlas under the trade names Emalex (R), Brij (R) and Laureth (R), and by Croda under the trade name Cetomacrogol (R).
• Lanolin alcohols are also known as wool fat alcohols and are a mixture of cholesterol, dihydrocholesterol and lanosterol.
• polyethers are, preferably free from impurities, and especially from other polyoxyalkylene ethers. They preferably contain at least 75%, most particularly at least 85% and especially at least 90% (weight) of the pure cholesteryl polyoxyethylene ether.
• a surface-active agent e.g. a polyoxyalkylene ether
• the amount present in the compositions according to the invention will depend on the surface-active agent used in particular, the form of administration (e.g. drops or spray) and the desired effect.
• the amount of surface-active agent employed is between ca. 2.0 and ca. 200 (preferably up to ca. 100, especially up to ca. 20), especially between ca. 5 and ca. 30 (preferably up to ca. 15) and in particular ca. 10 mg/ml.
• the liquid forms for nasal administration are preferably placed in an applicator, which is equipped with a device that enables the composition to be applied to the nasal mucous membrane, e.g. a nasal spray applicator.
• Such applicators are known per se and include those which are suitable for the administration of liquid preparations as drops or as a spray to the nasal mucous membrane. Since the dosing of the compounds of the invention should be as exact as possible, the use of spray applicators in which an exact control over the quantity administered is possible is generally preferred.
• Suitable appliance for administration are e.g. atomizers such as pump dispensers or aerosol cans. In the latter case, the applicator contains a composition according to the invention as well as a propellant which is suitable for use in a nasal spray applicator.
• the atomizer appliance is provided with an appropriate spray device which enables the composition to be applied to the nasal mucous membrane. Such devices are known in general.
• the container e.g. a nasal spray applicator
• the container may contain a quantity of the composition which is sufficient for a single nasal dose or for administration of several doses, e.g. over a period of several days or weeks.
• the amounts of the individual doses will preferably correspond to the above-mentioned doses.
• Applicators as defined above are preferably spray applicators for nasal usage. They preferably enable the composition contained there in to be administered in single doses of ca. 0.05 to ca. 0.15 ml, e.g. ca. 0.1 ml.
• compositions as well as the individual components 1,2 and 3 for use in an applicator, are those which have been previously described.
• the dosages which are suitable for use similarly correspond to the dosages given previously.
• the invention relates to a process for the production of a liquid form for nasal administration, containing
• a liquid diluent or a carrier which is suitable for administering to the nasal mucous membrane, as well as optionally a surface-active agent which is suitable for administering to the nasal mucous membrane characterised in that the components are intimately mixed together, and if desired, the composition obtained is placed in an applicator which is provided with a spray device which enables the composition thus obtained to be administered to the nasal mucous membrane.
• a sponge SPONGO-STAN
• the composition obtained may be soaked with the composition obtained and the soaked sponge can be inserted into the nostrils.
• composition according to the invention can be determined in the usual way.
• compositions according to the invention containing benzalkonium chloride are stable towards contamination by germs, e.g. as in standard tests such as those described by S. Urban et al. in Zbl. Bakt. Hyg. I Abt. Orig. B. 1972,478-484 (1981) and S. Urban, Acta Pharm. Technol.22,247-253 (1976).
• the cell count of the standard bacteria namely E. coli ATCC 8739, Pseud. aeruginosa ATCC 9027, Staph. aureus ATCC 6538, Strept. pyogenes ATCC 8668 and standard fungi Cand. albicans ATCC 10231, Sacch. cerevisae ATCC 9763, Aspergillus niger ATCC 16404 and Pen. steckil ATCC 10499, is reduced to 0.1% or less within 24 hours after injecting them with the composition, as can be shown in standard tests.
• the nasal spray composition of the following example 1 was kept for 3 months at 30° C. under a nitrogen atmosphere in a glass container, Pseud. aeruginosa ATCC 9027, Staph. aureus ATCC 6538, Strept. pyogenes ATCC 8668 and the fungi and, albicans ATCC 10231, Sacch. cerevisae ATCC 9763, Aspergillus niger ATCC 16404 and Pen. stechii ATCC 10499 were added until a cell count of ca. 2 ⁇ 10 5 organisms was reached in the injected liquid. Within 2 hours, the germ count had reduced to less than 0.1%, Within 4 weeks, the germs could no longer be detected.
• the compounds of the invention are administered in a galenic form, which is in the form of a powder and is introduced by blowing into the nostrils.
• the action of the compounds may be observed in spontaneously breathing rabbits which are anesthetized by a continuous infusion of sodium pentobarbital. Both vagi are intact and the systemie, arterial blood pressure, heart beat, breathing rate and platelet count are normal.
• Pulmonary embolism is produced by injecting 1 mg Sephadex G- 25 beads suspended in 0.2 ml dextran (6%) in 1 minute intervals in 6 animals into the right atrium.
• Pretreatment with the compounds of the invention i.v. at a dose of from 0.1 to 1 mg/kg produces a reduction in mortality and an improvement in the cardiovascular and breathing reflex parameters resulting during the developing lung embolism.
• the appropriate dosage will, of course, vary depending upon, for example, the compound of the invention employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at daily dosages from about 0.1 mg/kg to about 5 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 5 mg to about 50 mg of a compound of the invention conveniently administered, for example, in divided doses up to four times a day, preferably parenterally.
• the compounds are preferably administered in the form of a pharmaceutical composition e.g. as described above.
• the compounds of the invention may be administered for the lung embolism, by any conventional route, in particular enterally (if appropriate), preferably orally, e.g., in the form of tablets or capsules, or parenterally (if appropriate), e.g., in the form of injectable solutions or suspensions, or by the nasal route.
• the compounds of the invention also inhibit cancer therapy induced emesis in animals as indicated by standard tests, e.g. an inhibition of cis-platinin (10 mg/kg i.v.) induced emesis in ferrets at a dose of from about 0.005 to about 0.5 mg/kg i.v.
• the compounds of the invention furthermore are useful in the treatment of other serotonin HT 3 -induced gastro-intestinal disorders, e.g. as indicated in activity in tests indicated in EP 189002 at the same order of activity.
• the compounds are useful in the treatment of disorders resulting from increased peristaltic movements in the intestines and intestinal disorders arising or from activation of 5-HT 3 receptors, including diarrhea, e.g. secretary diarrhea, bacterial induced diarrhea, choleic diarrhea, traveller's diarrhea and psychogenic diarrhea, Crohn's disease, spastic colon and irritable bowel syndrome.
• diarrhea e.g. secretary diarrhea, bacterial induced diarrhea, choleic diarrhea, traveller's diarrhea and psychogenic diarrhea, Crohn's disease, spastic colon and irritable bowel syndrome.
• the compounds are also indicated to be useful in the treatment of disorders due to hypersecretion in the intestines, e.g. as a result of inflammation such as arising out of gastritis, peptic ulcer, biliary dyskinesia, appendicitis, ulcerative colitis and due to carcinoid syndrome leading to increased 5-HT secretion.
• the compounds are useful in the treatment of disorders arising from decreased peristaltic movements in the stomach and/or stomach disorders arising from activation of 5-HT 3 receptors, including those arising from decreased gastric emptying, including treatment of oesophageal motility disturbances, achalasia, hiatus hernia, cardia insufficiency, gastrooesophageal and gastroduodeinal reflux, stomach hypotonia and pylorus hyperplasia.
• the compounds are moreover useful in treatment of schizophrenia and mania and anxiety.
• the compounds may be administered in the same manner as for the rhinitis indications and in the same manner as described in European Patent Publication No. 189002.
• Toxicity and Tolerability studies may be effected in conventional manner with the compounds of the invention to determine the upper dosage.
• Toxicity studies may be effected for example in the rat and the dog over for example 26 weeks.
• Tablets containing the constituents as specified below were produced in conventional manner and are used in the indications specified above.
• Capsules containing the constituents as specified below are produced in conventional manner and are used in the indications specified above.
• a composition for injection is made up in conventional manner and is used at a dose of 10 mg a day.
• Capsules containing other weights can be formulated in conventional manner.
• the solution obtained is filtered (e.g. through a 0.2 ⁇ m filter) and filled into a nasal canister, or a gelatinous foam (SPONGOSTAN) is soaked with the solution. It is administered e.g. for the treatment of rhinitis, lung embolism or to improve the absorption of other active agents.
• SPONGOSTAN gelatinous foam
• the solution obtained is filtered (e.g. through a 0.2 ⁇ m filter) and filled into a nasal spray canister, or a gelatinous foam (SPONGOSTAN) is soaked with the solution. It is administered in analogous manner to that disclosed, in example 5.
• SPONGOSTAN gelatinous foam
• step b) compound in 300 ml methanol and 3.7 ml water is introduced within 1 hour gaseous HCl, whereby the temperature rises to 60° (cooling).
• the mixture is left at room temperature for 18 hours.
• the resulting white suspension is filtered, the filtrate is concentrated, rendered alkaline with potassium carbonate to a pH 10 and extracted with ether (3 times).
• the ether phase is washed with water and evaporated to give the title compound, as an oil, b.p. 72°-74°/0.13-0.15 mm Hg.
• a solution of 25.2 g of the step c) compound in 20 ml methanol is treated portionwise with 70 ml 2N aqueous NaOH solution within 30 minutes (pH at the end 13.2).
• the mixture is left at room temperature for 3 hours and then treated with the same amount of 2N HCl to a pH 5.8.
• the reaction mixture is chromatographed on about 300 ml amberlite TR 120 (H+form) using 10% NH 3 as eluant to give the title compound (recrystallised from ethanol/hexane), m.p. 222°-224° (decomp.).
• step d) compound in 50 ml CH 2 Cl 2 are added dropwise at about 15° 2.8 ml oxalyl chloride diluted with 5 ml CH 2 Cl 2 .
• the resulting white suspension is stirred 30 minutes at room temperature, diluted with 50 ml hexane, filtered and washed with CH 2 Cl 2 /hexane (1:2), to yield the hydrochloride of the title compound, decomp. from 205°.
• the aqueous phase is extracted with CH 2 Cl 2 and 10 to 15% C 2 H 5 OH (5 times).
• the evaporated exotracts (about 5 g) are dissolved in CH 2 Cl 2 +10% CH 3 OH and filtered (residue about 2 g).
• the solution is chromatographed on 250 g silica gel KG 004 using CH 2 Cl 2 +10% C 2 H 5 OH as an eluant whereby the title compound is obtained (800 g).
• the residue and 800 mg of the compound obtained by chromatography are together recrystalized from H 2 O/C 2 H 5 OH to give the hydrochloride of the title compound, m.p. 278°-280° (decomp.).
• step b) compound 100 ml toluene and 7.5 ml triethylamine are treated with 12.3 ml chloroformic acid benzyl ester. The mixture is heated 3 hours to 50°, then poured into 200 ml 0.1N HCl and extracted 3 times with CH 2 Cl 2 . The organic phase is dried (Na 2 SO 4 ) and evaporated to give the title compound as a colourless oil.
• step c) compound 9.1 g of the step c) compound are dissolved in 60 ml ethanol, treated with 60 ml 2N aqueous NaOH solution and refluxed 1 hour. After removal of ethanol by distillation, the remaining aqueous phase is acidified by addition of 10% tartaric acid and extracted with CH 2 Cl 2 . The combined organic phases are dried and evaporated to give the title compound as a yellowish foam.
• Methyl magnesium iodide prepared from 1.6 ml methyl iodide and 630 mg magnesium in 80 ml ether, is treated at room temperature with 1.5 g 6-methoxyindole in 70 ml ether. The mixture is heated 2 hours under reflux, then cooled to 0° and treated with 3.2 g of the step e) compound in 50 ml toluene. The reaction mixture is stirred 2 hours, poured into 2N hydrochloric acid and extracted 3 times with CH 2 Cl 2 .
• step f) compound in 30 ml CH 2 Cl 2 are treated at -78° with a solution of 0.8 ml boron tribromide in 10 ml CH 2 Cl 2 .
• aqueous sodium bicarbonate solution is added and the mixture extracted with n-butanol (3 times).
• the organic phases are evaporated and the residue is chromatographed on silica gel with CH 2 Cl 2 /CH 3 OH/aq. NH 3 (95:5:1>85:15:1) to yield the compound as colourless crystals, m.p.>280°.

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